Clinical depression and depressive symptoms associated with stressful life events have been found to be associated with a reduction in natural killer (NK) cytotoxicity, a parameter important in host resistance against tumor and virally infected cells. While psychologic states such as depression may have a role in the regulation of NK activity, little evidence has directly demonstrated the link between changes in the brain and alterations in natural cytotoxicity, even though NK cells can be influenced by the autonomic and neuroendocrine pathways. In depressed patients, the cerebrospinal fluid concentration of corticotropin releasing factor (CRF) is significantly elevated as compared to control subjects. Depression-related suppression of natural cytotoxicity might be coordinated by CRF if this neuropeptide indeed is a physiological central nervous system regulator with integrative actions on endocrine, autonomic, and visceral functions. The proposed work poses an animal model involving the central administration of CRF to further clarify the link between depression and the immune system and to provide direct evidence that changes in the brain can be communicated to NK cells via at lest one pathway, the autonomic nervous system. Our preliminary findings that intravesicular CRF reduces NK activity, together with the observation that ganglionic blockade completely antagonizes this effect, will be extended by defining central neuroanatomic sites of action, an efferent pathway from the brain, and cellular alterations involved in the reduction of NK activity by CRF. This research will include the following aims: 1) the effect of intraventricular CRF on NK activity will be further characterized by examining its time course of action and the effects of various regimens of repeated CRF treatment; 2) direct intracerebral injections of CRF will systematically evaluate putative central sites of action; 3) converging evidence will be provided of the role of sympathetic nervous pathways in the modulation of NK activity by CRF; 4) the immunologic mechanisms involved in altering NK activity will be defined including the reduction of cytotoxic activity at the cellular level in a cell population enriched for large granular lymphocytes. In summary, the findings of this study have the potential to provide direct evidence that CRF-induced changes in the brain are communicated to NK cells via the autonomic nervous system; thus, further clarifying the link between depression, psychological processes and natural cytotoxicity.